Mutation report: complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa.

Uniparental disomy denotes a situation when an individual has inherited two copies of a specific chromosome from a single parent. Uniparental disomy has been demonstrated to be involved in the pathogenesis of recessively inherited diseases in rare cases. Here we report a patient of Japanese origin with Herlitz junctional epidermolysis bullosa (OMIM no. 226700), who died at the age of 8 mo from complications of the disease. The mutation analysis revealed that the proband was homozygous for a nonsense mutation C553X in the LAMC2 gene encoding the gamma2 chain of laminin 5. The father was a heterozygous carrier of this mutation whereas the mother had two normal alleles of this gene. The patient showed homozygosity for 15 known intragenic polymorphisms in the LAMC2 gene. Furthermore, genotype analysis, performed from the parents and the proband, using 16 microsatellite markers spanning the entire chromosome 1, revealed that the patient was homozygous for all markers tested, and that these alleles originated from the father. Among the 16 markers, eight were fully informative for the absence of the maternal chromosome 1 in the proband, suggesting that the patient had complete paternal isodisomy of this chromosome. Thus, the Herlitz junctional epidermolysis bullosa phenotype in this patient is caused by homozygous LAMC2 mutation C553X that is of paternal origin and results from nondisjunction and uniparental disomy involving monosomy rescue. This is a novel mechanism resulting in Herlitz junctional epidermolysis bullosa and has implications for assessment of the risk in subsequent pregnancies.